Electrophilic substitution rate-determining step

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

The isotope effect in the bromination of 7V,iV-dimethylaniline in aqueous acid implies dissimilar mechanisms for the ortho and the para substitution. The rate-determining step could well involve, among other factors, fission or lengthening of the C—H bond in ortho bromination, but this is unlikely in para bromination. The di-methylamino group and bromine are believed to form an intermediate complex in these reactions, which appears to decrease the velocity of substitution with additional electrophile. Recent quantitative measurements, in electrophilic bromination , have reached the conclusion that the NMe2 group activates the para position of the ring ten times more than the ortho position. 

The active electrophile is formed by a subsequent reaction, often involving a Lewis acid. As discussed above with regard to nitration, the formation of the active electrophile may or may not be the rate-determining step. Scheme 10.1 indicates the structure of some of the electrophihc species that are involved in typical electrophilic aromatic substitution processes and the reactions involved in their formation. 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

The rate-determining step is the electrophilic aromatic substitution as in the closely related Friedel-Crafts reaction. Both reactions have in common that a Lewis acid catalyst is used. For the Blanc reaction zinc chloride is generally employed, and the formation of the electrophilic species can be formulated as follows ... 

Systematic studies of the selectivity of electrophilic bromine addition to ethylenic bonds are almost inexistent whereas the selectivity of electrophilic bromination of aromatic compounds has been extensively investigated (ref. 1). This surprising difference arises probably from particular features of their reaction mechanisms. Aromatic substitution exhibits only regioselectivity, which is determined by the bromine attack itself, i.e. the selectivity- and rate-determining steps are identical. 

Isotope Effects. If the hydrogen ion departs before the arrival of the electrophile (SeI mechanism) or if the arrival and departure are simultaneous, there should be a substantial isotope effect (i.e., deuterated substrates should undergo substitution more slowly than nondeuterated compounds) because, in each case, the C—H bond is broken in the rate-determining step. However, in the arenium ion mechanism, the C—H bond is not broken in the rate-... 

Cinnamyl alcohols substituted at the para carbon atom lend support to the mechanism in which the rate-determining step is the attack of the electrophilic oxygen atom the rate increases with the electron donicity of X, see Figure 14.7 [2]. 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

Problem 11.3 How does the absence of a primary isotope effect prove experimentally that the first step in aromatic electrophilic substitution is rate-determining ... 

A few examples are known in which the second step of an electrophilic aromatic substitution is rate-determining. For example, 67 is brominated by Br2 and BrOH at approximately the same rate, even though the latter is usually much the more reactive reagent. Moreover, the rate of reaction is first-order in base. These facts point to the two-step mechanism of Equation 7.70 with the second step ratedetermining.169... 

The overall mechanistic picture of these reactions is poorly understood, and it is conceivable that more than one pathway may be involved. It is generally considered that cycloheptatrienes are generated from an initially formed norcaradiene, as shown in Scheme 30. Equilibration between the cycloheptatriene and norcaradiene is quite facile and under acidic conditions the cycloheptatriene may readily rearrange to give a substitution product, presumably via a norcaradiene intermediate (Schemes 32 and 34). When alkylated products are directly formed from the intermolecular reaction of carbenoids with benzenes (Scheme 33 and equation 36) a norcaradiene considered as an intermediate alternatively, a mechanism may be related to an electrophilic substitution may be involved leading to a zwitterionic intermediate. A similar intermediate has been proposed143 in the intramolecular reactions of carbenoids with benzenes, which result in substitution products (equations 37-40). It has been reported,144 however, that a considerable kinetic deuterium isotope effect was observed in some of these systems. Unless the electrophilic attack is reversible, this would indicate that a C—H insertion mechanism is involved in the rate-determining step. 

Most aromatic substitution reactions conform to a simple mechanism. In the rate-determining step, a new bond is formed between an aromatic carbon atom and the electrophilic reagent yielding an intermediate... 

These conclusions have been confirmed experimentally,36 for both electrophilic and nucleophilic substitution. There seems no doubt that structures such as IH are stable entities rather than transition states. Moreover, as Melander and others have shown,36 the absence of deuterium isotope effects in most electrophilic substitutions indicates that in such cases the transition state must be VII rather than VIII. The rate-determining step in the reaction is the formation of the intermediate (III). 

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